The present invention relates to novel four and/or six substituted 5-hydroxy-2,3-dihydrobenzofuran and analogs useful as inhibitors of leukotriene biosynthesis.
A number of 5-hydroxy2,3-dihydrobenzofurans have been known to have anti inflammatory activity. U.S. Pat. No. 4,558,067 issued Thompson, et al., on Dec. 10, 1985 discloses sulfur containing phenylthiomethyl-6-hydroxy-2,3-dihydrobenzo pyran and analogs thereof. U.S. Pat. No. 4,537,903 issued to Chang, et al., on Aug. 27, 1985, U.S. Pat. No. 4,686,235 issued to Chang, et al., on Aug. 11, 1987 and application 039,407 filed Apr. 17, 1987 now U.S. Pat. No. 4,778,818 disclose substituted cinnamyl-2,3-dihydrobenzofuran and analogs thereof. U.S. Pat. No. 4,563,476 issued to Chang, et al., on Jan. 7, 1986 discloses substituted-5-hydroxy-2,3-dihydrobenzofurans, wherein the substituent is linked to the benzofuran via a methylamine group. U.S. Pat. No. 4,713,393 issued to Chang, et al., on Dec. 15, 1987 discloses substituted phenyl-2,3-dihydrobenzofurans wherein phenyl substituents are linked to the benzofuran via a propyl moiety.
These patents, however, do not disclose the novel compound of the present invention nor do they disclose the ability of these compounds to inhibit leukotriene biosynthesis in vitro, by the polymorphonuclear leukocytes assay.
During the progression of inflammatory conditions, there is generally an appearance and/or presence of macrophages and lymphocytes, especially polymorphonuclear leukocytes. These cells are known to secrete various products in response to inflammatory stimuli. The arachidonic acid oxygenation products, in particular, have been identified as critical mediators of various inflammatory conditions. Inhibition of arachidonic acid oxidation by enzyme inhibition has been explored as effective therapy. For example, non-steroidal anti inflammatory drugs (NSAID) such as aspirin, indomethacin and diflunisal are known cyclooxygenase inhibitors which inhibit the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes.
Recently, it has been observed that certain leukotrienes are responsible for diseases related to immediate hypersensitivity reactions such as human asthma, allergic disorders, and skin diseases. In addition, certain leukotrienes and derivatives thereof are believed to play an important role in causing inflammation (B. Samuelsson, Science, 220, 568 (1983); D. Baily et al, Ann. Rpts Med. Chem., 17, 203 (1982)).
Accordingly, pharmacological agents which are capable of inhibiting the formation or the release of leukotrienes and thereby interfere with the function of macrophages, or polymorphonuclear leukocytes, may also be effective in the treatment of various inflammatory conditions, e.g., pain, fever, rheumatoid arthritis, osteoarthritis, bronchial inflammation, inflammatory bowel disease, asthma, allergic disorders, skin diseases, cardiovascular disorder, glaucoma, emphysema, acute respiratory distress syndrome, spondylitis, lupus, gout, and psoriasis.
The human polymorphonuclear leukocytes assay, has been found to be a useful indicator of the ability of compounds to inhibit leukotriene biosynthesis. Known inhibitors of leukotriene biosynthesis agents such as Phenidone and Nordihydroguaiaretic acid, for example, are active in this assay (C. J. Blackwell and R. J. Flower, Prostaglandins, 16, 417 (1978); J. Chang, M. D. Skowronek, M. L. Cherney and A. J. Lewis, Inflammation, 8, 143 (1984)).